Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers.

Background: Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions.

Methods: We conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients.

Silver In Situ Hybridization for the Rapid Assessment of MDM2 Amplification in Soft Tissue and Bone Tumors. Validation Based on an Audit of 192 Consecutive Cases Evaluated by Silver In Situ Hybridization and Fluorescence In Situ Hybridization.

The discovery of almost invariable mouse double minute 2 (MDM2) amplification among atypical lipomatous tumors (ALT)/well-differentiated liposarcoma and dedifferentiated liposarcoma is incorporated into the contemporary diagnostic workup of fatty lesions. MDM2 amplifications are also found frequently in intimal sarcomas and in low-grade osteogenic sarcoma. At present, fluorescence in situ hybridization (FISH) is the reference test for MDM2 assessment.

Causes of ring-related leg injuries in birds - evidence and recommendations from four field studies.

One of the main techniques for recognizing individuals in avian field research is marking birds with plastic and metal leg rings. However, in some species individuals may react negatively to rings, causing leg injuries and, in extreme cases, the loss of a foot or limb. Here, we report problems that arise from ringing and illustrate solutions based on field data from Brown Thornbills (Acanthiza pusilla) (2 populations), Siberian Jays (Perisoreus infaustus) and Purple-crowned Fairy-wrens (Malurus coronatus).

Potent and selective nonpeptidic inhibitors of procollagen C-proteinase.

6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux.

Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.

1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids.

Integrative pharmacology and drug discovery--is the tide finally turning?

In vivo animal experiments are essential (and a regulatory requirement) to demonstrate the potential efficacy, safety and pharmacodynamic/pharmacokinetic profile of candidate drugs. However, the number of pharmacologists (and other bioscientists) with integrative (in vivo) pharmacology skills has been in decline for a number of years, as have the opportunities for students to learn such skills. This article reviews some recent initiatives that are underway to rebuild this essential skills base in the United Kingdom and the United States.

Effect of endothelin antagonists on the renal haemodynamic and tubular responses to ischaemia-reperfusion injury in anaesthetised rats.

In this investigation we have evaluated whether blockade of endothelin receptors influenced the renal haemodynamic and excretory responses to a period of ischaemia and reperfusion in the anaesthetised rat. The renal artery was occluded for 30 min and renal haemodynamic and excretory function followed for 90 min of reperfusion while either saline, the non-selective endothelin 1 receptor (ET(A)/ET(B)) antagonist SB209670 or the selective ET(A) receptor antagonist UK-350,926 was infused. In the post-ischaemic period, renal cortical and medullary perfusions were reduced by 40-50 %.

Inducible expression of human endoglin during inflammation and wound healing in vivo.

Objective: Because angiogenesis and inflammation are intimately associated and endoglin is required for angiogenesis, we wished to determine whether it also plays a role in inflammation.

Methods: Using an immunohistochemical approach, we examined spatial and temporal changes in endoglin expression during inflammation and angiogenesis.

Results: We found low levels of endoglin expression in quiescent endothelium in a range of normal adult human tissues.

The effect of endothelin antagonists on renal ischaemia-reperfusion injury and the development of acute renal failure in the rat.

Background: It is recognized that endothelins are released in response to hypoperfusion and anoxia of the kidney and may be responsible for the consequent deterioration in renal function. This study examined the ability of a non-selective (SB209670) and ET(A)-selective (UK-350,926) endothelin antagonist to attenuate ischaemia-induced renal failure in unilaterally nephrectomized rats.

Methods: The animals were anaesthetized, drug infusion commenced, and the renal artery occluded for 30 min.

Strand displacement amplification and homogeneous real-time detection incorporated in a second-generation DNA probe system, BDProbeTecET.

Background: Amplified DNA probes provide powerful tools for the detection of infectious diseases, cancer, and genetic diseases. Commercially available amplification systems suffer from low throughput and require decontamination schemes, significant hands-on time, and specially trained laboratory staff. Our objective was to develop a DNA probe system to overcome these limitations.

The effect of alpha 1 adrenoceptor antagonist prazosin on capillary supply, blood flow and performance in a rat model of chronic muscle ischaemia.

Objective: This study explores whether the a1 blocker prazosin improves capillarisation, blood flow and muscle performance in chronically ischaemic muscles.

Design: Rat skeletal muscles were made ischaemic by unilateral ligation of the common iliac artery. The animals received prazosin and muscle blood flow, performance and capillary supply were studied 2 or 5 weeks later.

In vivo characterisation of ZM 241385, a selective adenosine A2A receptor antagonist.

The in vivo characterisation of ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-+ ++ylamino] ethyl)phenol), a novel, non-xanthine, selective adenosine A2A antagonist is described. In anaesthetised dogs ZM 241385 (i.v.

The effect of thermal deactivation on the properties and processing characteristics of E. coli.

Recombinant microorganisms are often employed to produce proteins of commercial significance. It is important to render such organisms non-viable before culture fluids are released from the fermenter. Thermal deactivation is a superficially attractive option because of its simplicity.

Characterization of adenosine receptors in the rat isolated aorta.

1. Adenosine and its analogues relaxed the isolated rat aorta by an endothelium-dependent mechanism with an order of potency of 5'-N-ethylcarboxamidoadenosine (NECA) > 2-(p-(2-carboxy-ethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosi ne (CGS 21680) > adenosine = N6-(2-(4-amino-phenyl)ethyl)adenosine (APNEA) = N6-cyclopentyladenosine (CPA) > 5'-methylthioadenosine (MTA), although the maximal response achieved by CGS 21680 was less than that achieved by NECA. 2.

Simultaneous determination of tacrine and 1-hydroxy-, 2-hydroxy-, and 4-hydroxytacrine in human plasma by high-performance liquid chromatography with fluorescence detection.

An analytical method was developed for the simultaneous reversed-phase (cyano) high-performance liquid chromatographic determination with fluorescence detection of tacrine and 1-hydroxy-, 2-hydroxy-, and 4-hydroxytacrine in human plasma. Alkalinized human plasma samples were extracted with a mixture of chloroform/l-propanol (90:10, v/v). Extraction recoveries generally ranged from 68% to 83% for all four compounds and did not appear to be concentration dependent over the range examined.

Myocardial infarction and purine transport inhibition in anaesthetised ferrets.

The potential cytoprotective effect of the purine transport inhibitor S-(p-nitrobenzyl)-6-thioinosine (NBTI) in a model of myocardial ischaemia and reperfusion was investigated in the anaesthetised ferret. The left anterior descending coronary artery (LAD) was occluded for 90 min, producing ischaemia in 53 +/- 3% of the left ventricular free wall, followed by 240 min reperfusion. NBTI (0.

Adenosine receptor subtypes.

The numerous and widespread effects of adenosine provide both an opportunity for the development of novel therapeutic agents acting via adenosine receptors and the challenge of achieving selectivity of action. The feasibility of achieving selectivity is enhanced if receptor subtypes can be identified. Biochemical, functional and receptor-cloning studies are beginning to provide convergent data supporting the existence of A1, A2A, A2B and A3 receptors.

Further characterization of the protective effect of 8-cyclopentyl-1,3-dipropylxanthine on glycerol-induced acute renal failure in the rat.

In the rat, treatment with the alkylxanthine 8-cyclopentyl-1,3-dipropylxanthine (CPX) at a dose of 0.1 mg kg-1 antagonizes adenosine-induced falls in renal blood flow and reduces the severity of glycerol-induced acute renal failure. Treatment of glycerol-injected rats with 0.

Amelioration of cisplatin-induced acute renal failure with 8-cyclopentyl-1,3-dipropylxanthine.

1. The effect of the selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), on the development of cisplatin-induced acute renal failure was investigated in the rat. 2.

The effect of 8-cyclopentyl-1,3-dipropylxanthine on the development of cyclosporin-induced acute renal failure.

The effect of the selective A1-adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX, 0.1 mg kg-1 i.v.

Diuretic and saliuretic effects of 1,3-dipropyl-8-cyclopentylxanthine, a selective A1-adenosine receptor antagonist.

We have previously shown that 8-phenyltheophylline (8-PT), a non-selective antagonist at adenosine A1- and A2-receptors, has a diuretic effect. In this study, the diuretic and adenosine antagonist effects of the A1-receptor selective compound 1,3-dipropyl-8-cyclopentylxanthine (CPX) have been examined in the conscious rat. CPX (0.

The role of adenosine in exercise hyperaemia of the gracilis muscle in anaesthetized cats.

1. A number of metabolites have been proposed to control the vascular tone of skeletal muscle during exercise. The present study was designed to investigate the role of adenosine in this response by determining the effect of the adenosine receptor antagonist 8-phenyltheophylline.